The Kidney, Hypertension, Pregnancy and Inflammation

肾脏、高血压、怀孕和炎症

• 批准号: 8681487
• 负责人: Babbette LaMarca
• 金额: $ 30.88万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8681487
• 关键词: Acute; Address; Affect; Angiotensin II; Animals; Antibody Formation; Autoantibodies; B-Lymphocytes; Blood Pressure; Blood Vessels; CD4 Antigens; CD4 Positive T Lymphocytes; Cell Culture Techniques; Cells; Cessation of life; Chronic; Complement; Data; Development; Disease; Endothelial Cells; Endothelin-1; Event; Excretory function; Functional disorder; Helper-Inducer T-Lymphocyte; Hypertension; IL17 gene; Immunologic Memory; In Vitro; Inflammation; Inflammatory; Infusion procedures; Ischemia; Kidney; Laboratories; Lead; Link; Lymphocyte; Lymphocyte Depletion; Mediating; Modeling; Molecular; Morbidity - disease rate; Mothers; Natriuresis; Oxidative Stress; Pathogenesis; Pathway interactions; Perfusion; Perinatal; Physiological; Postpartum Period; Pre-Eclampsia; Pregnancy; Pregnant Women; Production; Proteinuria; Rattus; Reactive Oxygen Species; Receptor Activation; Receptor, Angiotensin, Type 1; Regulatory T-Lymphocyte; Renal Plasma Flow; Reporting; Role; Severities; Signal Pathway; Stimulus; T-Cell Activation; T-Lymphocyte; Techniques; Testing; Woman; arteriole; base; blood pressure regulation; cytokine; endothelial dysfunction; hemodynamics; immune activation; in vivo; inflammatory marker; neutrophil; novel; pregnancy hypertension; pregnant; pressure; receptor; release factor; response; vasoconstriction

DESCRIPTION (provided by applicant): Chronic activation of immune mechanisms contributes to the pathophysiology of preeclampsia, hypertension during pregnancy. Preeclamptic women have elevated circulating cytokines, neutrophils and lymphocytes producing an agonistic autoantibody to the angiotensin II type I receptor (AT1-AA). However, the exact pathway linking placental ischemia and immune activation with the development of hypertension during pregnancy has yet to be clearly defined. One possible mechanism is that chronic inflammation resulting in the AT1-AA promotes oxidative stress and endothelial dysfunction leading to altered renal hemodynamics and reduced renal pressure natriuresis by enhanced interactions with Angiotensin II and the Angiotensin II type 1 receptor. We have shown that reduced uterine perfusion pressure (RUPP) in pregnant rats, a rat model of preeclampsia, is an important stimulus for the production of the AT1-AA. Moreover, hypertension produced by RUPP is associated with enhanced inflammatory cytokines, endothelin-1 (ET-1) and reactive oxygen species (ROS) and reductions in renal plasma flow, GFR, and renal excretory function. Our preliminary data indicate the RUPP is associated with elevated lymphocytes and that depletion of these lymphocytes blunts production of the AT1-AA, ET-1 and hypertension in RUPP rats. Furthermore, our preliminary data supports the hypothesis that interactions between AT1-AA with the AT1 receptor, enhances renal microcirculatory and vascular sensitivity to ANGII. The central hypothesis to be tested in this proposal is hypertension in response to placental ischemia in pregnant rats is associated with T helper cell activation which in turn mediate the production of AT1-AA via B lymphocytes. In addition, we propose that the AT1-AA and ANGII interact via the AT1 receptor to enhance the production of ET-1 and ROS leading to decreases in renal hemodynamics and increases in blood pressure during pregnancy. To test this hypothesis an integrative physiological approach complemented with molecular, immunological, in vitro cell culture and in vivo techniques will be used to address the following 3 specific aims: 1) Does inhibited CD4+T lymphocyte regulatory mechanism in response to placental ischemia lead to endogenous AT1-AA mediated hypertension during pregnancy?2) To test the hypothesis that effector CD4+Thelper/TH17 mediated AT1-AA production increases blood pressure and decreases renal hemodynamics in response to placental ischemia in pregnant rats 3) To test the hypothesis that AT1-AA enhances renal and blood pressure sensitivity to ANG II in pregnant rats.

描述（由申请人提供）：免疫机制的慢性激活有助于先兆子痫、妊娠期高血压的病理生理学。先兆子痫女性的循环细胞因子、中性粒细胞和淋巴细胞升高，产生针对血管紧张素 II I 型受体 (AT1-AA) 的激动性自身抗体。然而，胎盘缺血和免疫激活与妊娠期高血压发生之间联系的确切途径尚未明确。一种可能的机制是，导致 AT1-AA 的慢性炎症会促进氧化应激和内皮功能障碍，从而导致肾血流动力学改变，并通过增强与血管紧张素 II 和血管紧张素 II 1 型受体的相互作用来降低肾压力尿钠排泄。我们已经证明，妊娠大鼠（先兆子痫的大鼠模型）中子宫灌注压（RUPP）降低是 AT1-AA 产生的重要刺激因素。此外，RUPP 产生的高血压与炎症细胞因子、内皮素-1 (ET-1) 和活性氧 (ROS) 的增强以及肾血浆流量、GFR 和肾排泄功能的降低有关。我们的初步数据表明，RUPP 与淋巴细胞升高有关，并且这些淋巴细胞的消耗会减弱 RUPP 大鼠中 AT1-AA、ET-1 的产生和高血压。此外，我们的初步数据支持这样的假设：AT1-AA 与 AT1 受体之间的相互作用增强肾微循环和血管对 ANGII 的敏感性。该提案要测试的中心假设是妊娠大鼠胎盘缺血引起的高血压与 T 辅助细胞激活相关，而 T 辅助细胞激活又通过 B 淋巴细胞介导 AT1-AA 的产生。此外，我们认为 AT1-AA 和 ANGII 通过 AT1 受体相互作用，增强 ET-1 和 ROS 的产生，导致妊娠期间肾脏血流动力学下降和血压升高。为了检验这一假设，将采用一种辅以分子、免疫学、体外细胞培养和体内技术的综合生理学方法来解决以下 3 个具体目标：1) 响应胎盘缺血而抑制 CD4+T 淋巴细胞调节机制是否会导致妊娠期间内源性 AT1-AA 介导的高血压？2) 检验效应器的假设 CD4+Thelper/TH17 介导的 AT1-AA 产生会增加妊娠大鼠胎盘缺血的血压并降低肾血流动力学 3) 检验 AT1-AA 增强妊娠大鼠肾脏和血压对 ANG II 的敏感性的假设。